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New Gene Therapy May Improve Parkinsonís Motor Symptoms

- Jan 09 2014

A new surgical intervention applying gene therapy that works by reprogramming brain cells so that they produce dopamine was shown to be safe and, potentially, to improve movement symptoms in people with advanced Parkinson’s disease (PD), according to a recent study. The results of this early-phase clinical trial were published in the January 10 issue of The Lancet.

Levodopa, commonly taken as carbidopa/levodopa (Sinemet®), is the gold standard therapy for PD motor symptoms such as tremor, stiffness, and slowness of movement. For individuals who have taken levodopa for many years, the amount of the drug that reaches the brain is highest soon after taking a pill and then rapidly tapers off, causing the motor symptoms of Parkinson’s to return, a problem known as “wearing off.” In addition, many individuals experience uncontrollable twisting and writhing movements when they take levodopa, a problem termed dyskinesias.

The gene therapy tested in this study, called ProSavin, is a Parkinson’s therapy that combines the genes for three enzymes important in the manufacture of dopamine, the key neurotransmitter that is missing in Parkinson’s disease. The technique involves inserting a large quantity of these genes into the basal ganglia region of the brain in order to coax the cells to produce a continuous supply of dopamine.

Led by Stéphane Palfi, M.D., Ph.D., from Groupe Henri-Mondor Albert-Chenevier in Créteil, France, the researchers injected the genes into the brains of 15 people with advanced PD, age 48 to 65 years, who had experienced wearing off and dyskinesias in response to levodopa treatment. All of the participants were aware that they were receiving the treatment. The first three study participants to receive the treatment received a low dose. When that was deemed safe, the scientists gave six additional study participants a higher dose, and finally, an additional six people got the highest dose. In addition, at the start of the study, participants’ movement symptoms were assessed using a standard test, the Unified Parkinson’s Disease Rating Scale (UPDRS), when they were taking and not taking levodopa.

Results

During the first 12 months of follow-up, participants reported no serious side effects. The most common side effect was increased dyskinesias while taking levodopa. Reducing the levodopa dose alleviated this side effect.

At six months and 12 months after treatment with the gene therapy, study participants’ UPDRS scores off levodopa had improved, on average about 12 points.

What Does It Mean?

There have been several gene therapy trials in Parkinson’s. Some approaches have aimed to help the symptoms of the disease by enhancing the effect of levodopa while others have aimed to slow the progression of the disease. The present study falls into the first category: a gene therapy to improve the effect of oral levodopa.

The primary goal of the present study was to demonstrate long-term safety and tolerability of the gene therapy technique. In this small study, the investigators have shown that the technique is safe.

But does it work? And for how long? Individuals who underwent gene therapy experienced a modest improvement in their Parkinson’s symptoms, as well as an increase in dyskinesias, suggesting that the gene therapy worked to boost the effect of levodopa. However, as the investigators noted, “the magnitude of effects are within the placebo range reported in other clinical trials for Parkinson’s disease using surgical techniques.”

The participants in this study were not randomized between the treatment and a placebo group. As such, it is not possible to state that the treatment worked better than a placebo. All the participants knew they were receiving the treatment, and it is well known that surgical treatments create a large placebo effect that can last for more than 12 months. Simply placing lesions in the basal ganglia regions of the brain can help the motor symptoms of Parkinson’s and it is possible that the improvement seen was a result of the surgical procedure itself rather than the novel gene therapy.

A key question with all gene therapies is: will the injected genes continue to be expressed, and will they provide therapeutic effects over time? This 12-month study cannot answer these questions but it is noted that some of the patients in this study were followed for 48 months, and their Parkinson’s symptoms worsened over time.

Until ProSavin can be tested in larger, double-blinded clinical trials with longer clinical follow-up, researchers cannot be certain of its effectiveness. The study authors plan further work to optimize dose and method of delivery before planning another trial.

Learn More

Do you have questions about new PD therapies on the horizon or treating motor symptoms of Parkinson's? Contact PDF’s toll-free HelpLine at (800) 457-6676 or info@pdf.org or use our free resources below.